1-Hydroxybenzotriazole → Biphenyl-4-carboxylic acid (2-{4-[methyl-(2-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-2-oxo-ethyl)-amide

HRID 1093576Notes

Reaction equation

HRID 1093576 reaction equation
[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:52][N:53]([CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([F:63])([F:62])[F:61]>CN(C=O)C.O>[CH3:52][N:53]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([F:63])([F:61])[F:62])[CH:64]1[CH2:69][CH2:68][N:67]([C:11](=[O:13])[CH2:10][NH:9][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:66][CH2:65]1

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2629432-((4-Phenylphenyl)formamido)acetic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 66591695N-Methyl-N-(2-(trifluoromethyl)phenyl)piperidin-4-amine hydrochloride

Product 1

HCID 44235027Biphenyl-4-carboxylic acid (2-{4-[methyl-(2-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-2-oxo-ethyl)-amideYield 17.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.075 g, 0.00029 mol) in DMF (3 mL), was added DIPEA (0.1519 g, 0.00117 mol), HOBt (0.03981 g, 0.00029 mol) and EDCI.HCl (0.06758 g, 0.00035 mol) at ambient temperature. After 2 minutes methyl-piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine hydrochloride (0.06959 g, 0.00026 mol) was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed aqueous sodium bicarbonate solution followed by brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to afford 0.023 g (16%) of biphenyl-4-carboxylic acid (2-{4-[methyl-(2-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-2-oxo-ethyl)-amide. LCMS: 496.2 (M+1)+, 98.28%, 1H NMR (DMSO-d6): δ 8.6 (t, 1H), 7.56-7.3 (m, 4H), 7.8-7.6 (m, 7H), 7.98 (d, 2H), 4.4 (bs, 1H), 4.15 (d, 2H), 3.9 (bs, 1H), 3.2-2.9 (m, 2H), 1.7 (bs, 2H), 1.5-1.2 (m, 2H).

Workup

  1. extractionthe product was extracted with ethyl acetate
  2. washThe ethyl acetate layer was washed aqueous sodium bicarbonate solution
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customThe resulting residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-d425ca84d91d4be1954cacf20d5415a2
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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